February 2019

SERS-based detection of haptoglobin in ovarian cyst fluid as a point-of-care diagnostic assay for epithelial ovarian cancer.  J Perumal, AP Mahyuddin, G Balasundaram, D Goh, CY Fu, A Kazakeviciute, US Dinish, M Choolani, M Olivo. Cancer Management and Research 2019 Volume 2019:11 pp 1115—1124 https://doi.org/10.2147/CMAR.S185375   https://www.dovepress.com/sers-based-detection-of-haptoglobin-in-ovarian-cyst-fluid-as-a-point-o-peer-reviewed-article-CMAR

Purpose: To evaluate haptoglobin (Hp) in ovarian cyst fluid as a diagnostic biomarker for epithelial ovarian cancers (EOCs) using surface-enhanced Raman spectroscopy (SERS)-based in vitro diagnostic assay for use in an intraoperative setting.

Methods: SERS-based method was used to detect and quantify Hp in archived ovarian cyst fluids collected from suspicious ovarian cysts and differentiate benign tumors from EOCs. The diagnostic performance of SERS-based assay was verified against the histopathology conclusions and compared with the results of CA125 test and frozen sections.

Results: Hp concentration present in the clinical cyst fluid measured by SERS was normalized to 3.3 mg/mL of standard Hp. Normalized mean values for patients with benign cysts were 0.65 (n=57) and malignant cysts were 1.85 (n=54), demonstrating a significantly (P<0.01) higher Hp in malignant samples. Verified against histology, Hp measurements using SERS had a sensitivity of 94% and specificity of 91%. Receiver operating characteristic curve analysis of SERS-based Hp measurements resulted in area under the curve of 0.966±0.03, establishing the robustness of the method. CA125 test on the same set of patients had a sensitivity of 85% and specificity of 90%, while frozen section analysis on 65 samples had 100% sensitivity and specificity.

Conclusion: With a total execution time of <10 minutes and consistent performance across different stages of cancer, the SERS-based Hp detection assay can serve as a promising intraoperative EOC diagnostic test.

Risks of Ovarian, Breast, and Corpus Uteri Cancer in Women Treated With Assisted Reproductive Technology in Great Britain, 1991–2010 Data Linkage Study Including 2.2 Million Person Years of ObservationCL Williams, ME Jones, AJ Swerdlow, BJ Botting, MC Davies, I Jacobs, KJ Bunch, MF Murphy, AG Sutcliffe, Obstetrical & Gynecological Survey: February 2019 – Volume 74 – Issue 2 – p 89–90 https://journals.lww.com/obgynsurvey/fulltext/2019/02000/Risks_of_Ovarian,_Breast,_and_Corpus_Uteri_Cancer.16.aspx

doi: 10.1097/01.ogx.0000553097.89718.65

Assisted reproductive therapy such as exposure of women to supraphysiological levels of estradiol, exogenous gonadotropins, and multiple ovarian punctures are suspected to incur an increased risk of cancer. Studies investigating the carcinogenic effects of these exposures are largely inconsistent. Specific concern surrounds the potentially increased risks of breast, endometrial, and ovarian cancers.

This large population-based cohort study aimed to provide risk estimates for ovarian, breast, and corpus uteri cancer in women undergoing assisted reproduction. Data were obtained on all women undergoing assisted reproduction between 1991 and 2010 in Great Britain through the Human Fertilisation and Embryology Authority (HFEA). UK law mandates reporting of all assisted reproduction cycles to the HFEA, making this a very robust representation of the target population. Data on cancer prevalence in this population were obtained from the National Health Service Central Registers of England, Wales, and Scotland, and these were linked to HFEA records through a one-off linkage. The HFEA database was also used to obtain data on potential confounding variables including demographics, infertility diagnosis, parity, and treatment details. Follow-up was calculated from the date of first treatment to the date of any cancer diagnosis, death, emigration, or end of study. National incidence rates and person years of expected risk were used to calculate expected cancer rates. Standardized incidence ratios (SIRs) were calculated by comparison of observed outcomes versus expected outcomes.

A total of 255,786 women contributed 2,257,789 person years of follow-up for analysis. Median follow-up duration was 8.8 years, and median age at first treatment was 34.5 years. Subjects had a median of 1.8 stimulated cycles with 50,485 (20%) having more than 2 stimulated cycles. No increase in risk of breast cancer overall (SIR, 0.98; 95% confidence interval [CI], 0.94–1.01) or invasive breast cancer (SIR, 0.96; 95% CI, 0.92–1.00) posttreatment was observed. No overall increase in corpus uteri cancer was observed (SIR, 1.12; 95% CI, 0.95–1.30). A small increased risk of in situ breast cancer was observed (SIR, 1.15; 95% CI, 1.02–1.29), which was associated with the number of treatment cycles (P = 0.03). An overall increased risk of ovarian cancer was observed (SIR, 1.39; 95% CI, 1.26–1.53) with a trend of increasing risk with decreasing age at first treatment (P < 0.001). Significantly increased risks for ovarian cancer were also observed in women with diagnosis of female factor infertility particularly endometriosis (SIR, 2.31; 95% CI, 1.74–3.01) and tubal disease (SIR, 1.68; 95% CI, 1.43–1.97).

This large, national population-based study found that after assisted reproductive treatment, there was an increased risk of ovarian cancer and increased risk of situ breast cancer associated with increasing number of treatment cycles. No increased risks for corpus uteri or invasive breast cancer were observed.

The Molecular Profiling Lottery: More Accuracy, Less Precision, and No CostMJ Ratain. DOI: 10.1158/1078-0432.CCR-18-3513  Clinical Cancer Research 25, (4) 1136-1138.  http://clincancerres.aacrjournals.org/content/25/4/1136.article-info

The concept of complete molecular profiling to select investigational treatment options is appealing, theoretically allowing the matching of patients to investigational drugs specifically targeted to molecular features of each patient’s cancer. Although some patients do benefit from such a strategy, the vast majority do not.

In this issue of Clinical Cancer Research, Tuxen and colleagues report the results of the Copenhagen Prospective Personalized Oncology (CoPPO) study, which enrolled 591 patients, 500 of whom underwent biopsy for the purpose of individualizing investigational therapy (1, 2). The samples were extensively analyzed, including both whole-exome sequencing (WES) and quantitation of RNA expression of prespecified therapeutic targets. Although the study confirms the feasibility of molecular profiling, it does not provide evidence that this approach should be broadly utilized to prioritize investigational treatment options for patients with refractory advanced solid tumors.

The originally stated objective of the CoPPO study was to measure the percentage of patients who benefited from molecular profiling, using the same approach used by Von Hoff and colleagues (3), where benefit was defined as progression-free survival for the selected therapy that was at least 30% longer than that for the last prior regimen. Tuxen and colleagues appropriately conclude that the PFS ratio endpoint is highly flawed and cannot be used to assess the validity of a diagnostic approach, a refreshing conclusion.

So if the primary endpoint is invalid, how should one assess the results of the CoPPO study? Should one use an “intention to treat” analysis, where there were 500 patients who underwent biopsy, 15 (3%) of whom responded to the matched treatment? (while only 101 patients received “matched” therapy, one can reasonably assume that the remaining patients did not benefit from the molecular profiling.)

And if the response rate was 3%, is that good or bad, given that there were 15 patients (3%) who suffered serious biopsy complications? But were there really 15 patients who benefited from the molecular profiling itself? A closer look at the data suggest otherwise.

The 15 patients who had partial responses included seven with BRAF V600E mutations, all treated on studies of BRAF inhibitors in combination with one or more other drugs. Thus, there is no question these patients benefited, but because all patients had colorectal or non–small cell lung cancer, such information may have been available prior to entry in the study, as part of the standard molecular diagnostic workup of these diseases, and if so, the molecular profiling in the study—requiring rebiopsy—was unnecessary. Regardless, it is now common clinical practice to test for BRAF V600E mutations in these diseases, given the progress in treating this molecular subset of melanoma and other solid tumors (4).

In the remaining eight responders, the benefit of the rebiopsy for molecular profiling is even less clear. For example, 1 patient with gastric cancer that had previously been treated with capecitabine, oxaliplatin, and trastuzumab was enrolled on a study of epirubicin and trastuzumab because of the presence of ERBB2 R678Q. However, this has been suggested to be a marker of resistance to trastuzumab, not surprising as the patient had just received the drug. Given that epirubicin is an active agent in gastric cancer, trastuzumab probably only added toxicity, not to mention the risk of the biopsy.

Close review of the other responders also diminishes one’s enthusiasm for the benefit of broad molecular profiling. A patient with breast cancer responded to palbociclib and fulvestrant, although the identified molecular feature (CCND1 amplification) is likely irrelevant. A patient with EML4-ALK lung cancer responded to an ALK inhibitor, yet testing for EML4-ALK is now standard practice. Similarly, 2 patients with BRCA1 (breast) or BRCA2 (prostate) mutations responded to olaparib, yet one would not need rebiopsy today to test for BRCA mutations.

In addition, the actual tumor response is uncertain for at least 1 patient, the patient with adenoid cystic carcinoma (ACC) who was treated with a Notch inhibitor, presumably LY3039478. However, in the primary report of the phase I study of LY3039478 (5), there were no partial responses in ACC, as the only responder had breast cancer and the 1 patient with a 100% decrease in the target lesion actually had progressive disease due to the development of new lesions.

Thus, putting these results in context with what we know now, one cannot recommend obtaining a new tumor specimen for molecular profiling as a generalized strategy for prioritization of investigational agents. One can envision that this would be appropriate in select circumstances (Fig. 1), especially when there is a protocol that requires the presence of a particular mutation that is known to arise due to resistance to a previous agent, such as utilized in the development of EGFR T790M inhibitors. Furthermore, with advances in “liquid biopsies,” the risks of deep tissue biopsies can be avoided. One challenge is overcoming the political cache of “precision medicine,” particularly as oncologists are enthralled with the notion of precision. After all, most of us were trained to calculate body surface area (BSA) to the nearest hundredth of a square meter, despite the lack of evidence that BSA-based dosing is superior to alternative dosing strategies.

However, what we really need is accuracy; administering treatments that are effective, even if not tailored to the individual patient, because the drug is so effective. Furthermore, we do not need precise dosages, but simply dosages that are effective without undue toxicity. Of great importance, the effective dosage may be a fraction of the labeled (and often precise) dose recommended by the manufacturer.  We should also reconsider the cost-effectiveness of WES, in the absence of drugs indicated for specific molecular subsets known to be prevalent in a particular disease. Although there is no question that WES facilitates enrollment of patients on some clinical trials, the cost of such testing should perhaps be borne by the pharmaceutical industry, rather than by payors and patients. In particular, who should pay the cost of testing for very rare variants, such as NTRK fusions amenable to treatment with larotrectinib? How many patients will we need to test to identify 1 patient who will benefit from that drug?  One potential solution would be for the pharmaceutical industry to create and fund a nonprofit precompetitive entity that performs WES for all patients with cancer. Because this would identify patients who would be eligible to receive expensive drugs and/or participate in expensive trials of investigational drugs, this would be in the interest of the industry, patients, and physicians. It would also be in the interest of global regulatory agencies, which could review and approve a single test that would become the global standard-of-care, given that it would be provided for free to all patients with cancer. In an era where pharmaceutical companies are demonized daily, this would truly allow that industry to give something back to patients and payors. If not, perhaps payors should offer our patients the choice of WGS or repurposing the funds to purchase real lottery tickets, given current concerns regarding the increasing financial toxicity of modern oncology care.  One challenge is overcoming the political cache of “precision medicine,” particularly as oncologists are enthralled with the notion of precision. After all, most of us were trained to calculate body surface area (BSA) to the nearest hundredth of a square meter, despite the lack of evidence that BSA-based dosing is superior to alternative dosing strategies.  However, what we really need is accuracy; administering treatments that are effective, even if not tailored to the individual patient, because the drug is so effective. Furthermore, we do not need precise dosages, but simply dosages that are effective without undue toxicity. Of great importance, the effective dosage may be a fraction of the labeled (and often precise) dose recommended by the manufacturer.  We should also reconsider the cost-effectiveness of WES, in the absence of drugs indicated for specific molecular subsets known to be prevalent in a particular disease. Although there is no question that WES facilitates enrollment of patients on some clinical trials, the cost of such testing should perhaps be borne by the pharmaceutical industry, rather than by payors and patients. In particular, who should pay the cost of testing for very rare variants, such as NTRK fusions amenable to treatment with larotrectinib? How many patients will we need to test to identify 1 patient who will benefit from that drug?

One potential solution would be for the pharmaceutical industry to create and fund a nonprofit precompetitive entity that performs WES for all patients with cancer. Because this would identify patients who would be eligible to receive expensive drugs and/or participate in expensive trials of investigational drugs, this would be in the interest of the industry, patients, and physicians. It would also be in the interest of global regulatory agencies, which could review and approve a single test that would become the global standard-of-care, given that it would be provided for free to all patients with cancer. In an era where pharmaceutical companies are demonized daily, this would truly allow that industry to give something back to patients and payors. If not, perhaps payors should offer our patients the choice of WGS or repurposing the funds to purchase real lottery tickets, given current concerns regarding the increasing financial toxicity of modern oncology care.

Copenhagen Prospective Personalized Oncology (CoPPO)—Clinical Utility of Using Molecular Profiling to Select Patients to Phase I TrialsIV Tuxen, KS Rohrberg, O Oestrup, LB Ahlborn, AY Schmidt, I Spanggaard, JP Hasselby, E Santoni-Rugiu, C Westmose Yde, M Mau-Sørensen, FC Nielsen and U Lassen.  Clinical Cancer Research 25, (4) p1239-1247.  DOI: 10.1158/1078-0432.CCR-18-1780 http://clincancerres.aacrjournals.org/content/early/2018/09/29/1078-0432.CCR-18-1780

Purpose: We evaluated the clinical benefit of tumor molecular profiling (MP) to select treatment in the phase 1 setting. Experimental Design: Patients with advanced solid cancers and exhausted treatment options referred to a phase 1 unit were included in a prospective single-centre single-arm open-label study (NCT02290522), including ovarian cancers. Tumor biopsies were obtained for comprehensive genomic analysis including whole exome sequencing (WES) and RNA sequencing. When possible, patients were treated with regimen matched to the genomic profile. Primary endpoint was progression free survival. Results: From May 2013 to January 2017 a total of 591 patients were enrolled with 500 patients undergoing biopsy. Genomic profiles were obtained in 460 patients and a potential actionable target was identified in 352 (70%) of 500 biopsied patients. One hundred and one patients (20%) received matched treatment based on either gene mutations or RNA expression levels of targets available in early clinical trials or off-label treatment. Objective response according to RECIST1.1 was observed in 15/101 patients (0% CR, 15% PR) with a median PFS of 12 weeks (95% CI 9.9-14.4). Conclusions: Our study supports the feasibility of genomic profiling to select patients in the phase 1 setting and suggests that genomic matching can be beneficial for a minor subset of patients with no other treatment options. Randomized studies may validate this assumption.

Long-Term Survival in Patients Responding to Anti–PD-1/PD-L1 Therapy and Disease Outcome upon Treatment Discontinuation.  M-L Gauci, E Lanoy, S Champiat, C Caramella, S Ammari, S Aspeslagh, A Varga, C Baldini, R Bahleda, A Gazzah, J-M Michot, S Postel-Vinay, E Angevin, V Ribrag, A Hollebecque, J-C Soria, C Robert, C Massard and A Marabell.  Clinical Cancer Research 25 (3) 2019.  DOI: 10.1158/1078-0432.CCR-18-0793 http://clincancerres.aacrjournals.org/content/early/2018/10/06/1078-0432.CCR-18-0793

Purpose: Anti–PD-(L)1 can provide overall survival (OS) benefits over conventional treatments for patients with many different cancer types, including ovarian cancers. However, the long-term outcome of cancer patients responding to these therapies remains unknown. This study is an exploratory study that aimed to describe the long-term survival of patients responding to anti–PD-(L)1 monotherapy across multiple cancer types, including ovarian cancers.

Patients and Methods: Data from patients treated with an anti–PD-(L)1 monotherapy in a phase I trial at Gustave Roussy were retrospectively analyzed over a period of 5 years. All cancer types (n = 19) were included. Clinical and biological factors associated with response, long-term survival, and secondary refractory disease were studied.

Results: Among 262 eligible patients, the overall objective response rate was 29%. The median progression-free survival of responder patients (RP) at 3 months was 30 months, and the median OS of RP was not reached after a median follow-up of 34 months. In RPs, 3- and 5-year OS percentages were 84% and 64%, respectively. No death occurred in the 21 complete responders (CR) during the overall follow-up. However, many partial responders (PR) showed subsequent tumor relapses to treatment. Long responders (response ≥2 years) represented 11.8% of the overall population. These findings should be validated in further prospective studies.

Conclusions: There are currently no differences in therapeutic strategies between CRs and PRs to anti–PD-(L)1. We found a striking difference in OS between these two types of responses. Our results are in favor of evaluating patient stratification strategies and intensification of treatments when tumor lesions of a partial responder to immunotherapy stop improving.

Is Precision Medicine an Oxymoron?  SG Eckhardt, C Lieu. JAMA Oncol. 2019;5(2):142-143. doi:10.1001/jamaoncol.2018.509 https://jamanetwork.com/journals/jamaoncology/article-abstract/2713848

The initial results of the National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial were presented at the 2018 American Society of Clinical Oncology Annual Meeting. The NCI-MATCH trial is an ongoing phase 2 trial that seeks to determine whether targeted therapies for specific gene mutations will lead to objective responses agnostic to the primary cancer type. The trial features nearly 40 treatment arms, each of which aims to enroll at least 35 patients whose tumors have a specific genetic alteration. Individual arms rely on objective response as the primary end point, which also drives decisions about expansion beyond the first stage of accrual. Additional arms in the NCI-MATCH trial are currently enrolling, and several are in development.

Three cohorts from the NCI-MATCH trial were reported; patients with tumors harboring ERRB2/HER2 amplification, FGFR alterations, or PIK3CA mutations were treated with T-DM1, AZD4547, or taselisib, respectively. Objective response rates were low across all arms, ranging from 0% to 9.5%, with no agent reaching the prespecified threshold of notable clinical activity.1-3 Although there were patients with prolonged stable disease, this finding should be interpreted with caution because these were nonrandomized trials of patients with widely disparate prior therapy. Valid concerns raised by the investigators and discussants included the extensive prior therapy of many of the enrolled patients as well as co-occurring mutations, each of which could have limited the impact of targeted single-agent therapy.

The modest results reported for these NCI-MATCH arms stand in contrast to those of the neurotrophic tropomyosin receptor kinase (TRK) inhibitor, larotrectinib, which was associated with durable objective responses across a wide range of malignant neoplasms (75%) independent of their histologic features.4 In this case, fusions involving tropomyosin receptor kinase genes lead to chimeric proteins with constitutively activated or overexpressed kinase function conferring dominant oncogenic potential, similar to EML4-ALK (the fusion between echinoderm microtubule associated protein-like 4 and anaplastic lymphoma kinase) in non–small cell lung adenocarcinoma. However, unlike gene fusion events, the presence of other genetic alterations has not reliably led to tissue-agnostic activity, which may be due to differences in pathway activation and dependence among tumors, indicating that context may be important for some oncogenic pathways. This is exemplified by BRAF V600E mutations in melanoma compared with colorectal cancer. While vemurafenib demonstrated significant activity in BRAF V600E–mutated melanoma, similar response rates were not observed in colorectal cancer owing to feedback activation of epidermal growth factor receptor. Discordant results have also been observed in ERBB2/HER2-amplified breast and gastric cancer treated with trastuzumab and pertuzumab. In fact, taken as a whole, targeting receptors of the epidermal growth factor receptor family has taught us that patient selection is necessary but not sufficient to reliably predict tumor regression even in patients with similar histologies.

Perhaps unsurprisingly, the NCI-MATCH trial screened more than 6000 patients in a roughly 2-year period, highlighting the broad interest of patients and clinicians in the promise of molecularly driven studies. Unfortunately, this robust interest has not yielded globally robust results, in part because of the imprecision of precision medicine and biological naivete driving catchy phrases that oversimplify the malignant process. Nonetheless, the ability to engage a large population of patients and clinicians in the clinical trials process is encouraging and provides a valuable framework for future patient-selective trials. Regarding how tissue-agnostic results are then further tested and evaluated, an open forum is needed to discuss and develop clinical activity thresholds that are linked to clinical development algorithms. These must be developed within the context of other single-agent and combination strategies, including immunotherapy, so that we prioritize testing of the most promising approaches regardless of whether these approaches are labeled “precision medicine.” The upper and lower extremes of responses are easy to act on, whereas there is a tendency to ascribe more significance to a few durable responses with molecularly targeted agents, although a similar percentage could be observed with unselected chemotherapy or immunotherapy.

The preliminary results from the NCI-MATCH trial highlight a critical biological reality that has been known for some time: that genomic alterations do not always lead to oncogenic pathway activation or addiction and that targeting multiple driver and/or resistance pathways may be required for optimal antitumor efficacy. In fact, as we consider how to prioritize strategies for further testing, a better understanding of cancer biology is needed to optimize and define context-dependent oncogenic mutations and resistance mechanisms. There is no one-size-fits-all approach, but preclinical models, such as patient-derived xenografts and organoids, may help elucidate potential codrivers and resistance mechanisms so that rational combinations can be designed and tested to support clinical deployment. Tissue acquisition during a study, such as biopsy specimens harvested after disease progression, which were obtained in a subset of patients enrolled in the MATCH trial, are instrumental in characterizing changes associated with adaptive resistance. Overall, this strategy will require greater investment in systems biology to select patients and derive combinations based on a more informed signature while still acknowledging the inherent imprecision. Analyses of circulating tumor DNA may also provide insights regarding dynamic changes that correspond to drug response or resistance as has been observed with RAS mutations in patients with colorectal cancer treated with epidermal growth factor receptor inhibitors.6 The field of oncology drug development has witnessed immense progress based on the elegant science of many, and now is the time to minimize dogma and bias and tackle the complexity of preclinical and clinical drug development. This must be done to prioritize clinical trials in this notable era or risk launching poorly founded trials that preclude enrollment to studies of greater impact.

Do these MATCH results indicate that a molecularly driven agnostic approach is a failure? The answer is a qualified yes and no. There is no question that a higher efficacy rate was anticipated in these arms, but the trial does represent an initial step in attempting to leverage the knowledge of cancer biology to affect treatment across tumor types. The negative data presented signify a critical step in drug development and molecularly targeted approaches. The lack of single-agent activity is important to define and guide the next steps for target inhibition and highlights the importance of robust correlative studies on available samples. Negative trial data are most helpful when correlative studies generate data that lead to alternative hypotheses. When such correlative studies are not incorporated, essential information is lost, and we lose the iterative process of investigation—bench to bedside and back—that has resulted in major therapeutic advances in the field.

How do we view these results within the context of immunotherapy? The first-ever tissue- or site-agnostic US Food and Drug Administration approval was for pembrolizumab for tumors displaying high microsatellite instability or deficient mismatch repair. However, these results are parallel to those of molecularly targeted agents that regress tumors harboring oncogenic fusion proteins. Both approaches represent the extreme extent to which tumors may respond to molecular or immune blockade. These are the exemplars of biologically driven anticancer agents; however, lest one imagine that immunotherapy is going to be a better substrate for precision medicine approaches, the same challenges have been observed in terms of optimizing patient selection.7

In conclusion, there is no doubt that these MATCH results represent a well-intentioned and coordinated attempt to deploy precision medicine in oncology. These results, along with others, represent the continual evolution of imprecise cancer biology and thus should drive us toward integrative and iterative strategies that improve the outcomes for our patients.

Nomogram for Predicting Individual Survival After Recurrence of Advanced-Stage, High-Grade Ovarian Carcinoma. P Rose, JJ Java, R Salani, MA Geller, AA Secord, KS Tewari, DP Bender, DG Mutch, ML Friedlander, L Van Le, MW Method, CA Hamilton, RB Lee, RM Wenham, SR Guntupalli, M Markman, FM Muggia, DK Armstrong, MA Bookman, RA Burger, LJ Copeland.  Obstetrics & Gynecology 133(2), 2019, p 245–254. DOI: 10.1097/AOG.0000000000003086  https://journals.lww.com/greenjournal/Fulltext/2019/02000/Nomogram_for_Predicting_Individual_Survival_After.3.aspx?platform=hootsuite

OBJECTIVE: To analyze clinical prognostic factors for survival after recurrence of high-grade, advanced-stage ovarian–peritoneal–tubal carcinoma and to develop a nomogram to predict individual survival after recurrence.

METHODS: We retrospectively analyzed patients treated in multicenter Gynecologic Oncology Group protocols for stage III and IV ovarian–peritoneal–tubal carcinoma who underwent primary debulking surgery, received chemotherapy with paclitaxel and a platinum compound, and subsequently developed recurrence. Prognostic factors affecting survival were identified and used to develop a nomogram, which was both internally and externally validated.

RESULTS: There were 4,739 patients included in this analysis, of whom, 84% had stage III and 16% had stage IV ovarian carcinoma. At a median follow-up of 88.8 months (95% CI 86.2–92.0 months), the vast majority of patients (89.4%) had died. The median survival after recurrence was 21.4 months (95% CI 20.5–21.9 months). Time to recurrence after initial chemotherapy, clear cell or mucinous histology, performance status, stage IV disease, and age were significant variables used to develop a nomogram for survival after recurrence, which had a concordance index of 0.67. The time to recurrence alone accounted for 85% of the prognostic information. Similar results were found for patients who underwent second look laparotomy and had a complete pathologic response or received intraperitoneal chemotherapy.

CONCLUSION: For individuals with advanced-stage ovarian carcinoma who recur after standard first-line therapy, estimated survivals after recurrence are closely related to the time to recurrence after chemotherapy and prognostic variables can be used to predict subsequent survival.

Losartan treatment enhances chemotherapy efficacy and reduces ascites in ovarian cancer models by normalizing the tumor stroma.  Y Zhao, J Cao, A Melamed, M Worley, A Gockley, D Jones, HT Nia, Y Zhang, T Stylianopoulos, AS Kumar, F Mpekris, M Datta, Y Sun, L Wu, X Gao, O Yeku, MG. del Carmen, DR Spriggs, RK Jain, L Xu.  PNAS, 2019 116 (6) 2210-2219;  https://doi.org/10.1073/pnas.1818357116 https://www.pnas.org/content/116/6/2210

Abstract  In ovarian cancer patients, tumor fibrosis and angiotensin-driven fibrogenic signaling have been shown to inversely correlate with survival. We sought to enhance drug delivery and therapeutic efficacy by remodeling the dense extracellular matrix in two orthotopic human ovarian carcinoma xenograft models. We hypothesized that targeting the angiotensin signaling axis with losartan, an approved angiotensin system inhibitor, could reduce extracellular matrix content and the associated “solid stress,” leading to better anticancer therapeutic effect. We report here four translatable findings: (i) losartan treatment enhances the efficacy of paclitaxel—a drug used for ovarian cancer treatment—via normalizing the tumor microenvironment, resulting in improved vessel perfusion and drug delivery; (ii) losartan depletes matrix via inducing antifibrotic miRNAs that should be tested as candidate biomarkers of response or resistance to chemotherapy; (iii) although losartan therapy alone does not reduce tumor burden, it reduces both the incidence and the amount of ascites formed; and (iv) our retrospective analysis revealed that patients receiving angiotensin system inhibitors concurrently with standard treatment for ovarian cancer exhibited 30 mo longer overall survival compared with patients on other antihypertensives. Our findings provide the rationale and supporting data for a clinical trial on combined losartan and chemotherapy in ovarian cancer patients.

Significance  Despite initial responsiveness to chemotherapy, the overwhelming majority of advanced ovarian cancer patients relapse with resistant disease. Thus, developing more effective strategies for ovarian cancer treatment is a high clinical priority. Here, we report that targeting angiotensin signaling with losartan, an angiotensin receptor blocker, can reduce extracellular matrix in ovarian tumors and the associated physical barriers that normally hinder drug delivery and efficacy. These changes in the tumor microenvironment lead to improved response to chemotherapy, and, importantly, decrease ascites—a major burden for ovarian cancer patients. These preclinical findings are in concert with our retrospective analysis showing improved survival in patients receiving angiotensin system inhibitors concurrently with standard treatment for ovarian cancer and should be tested in a clinical trial.

Modernizing Clinical Trials for Patients With Cancer.  NE Sharpless, JH Doroshow.  JAMA. 2019;321(5):447-448. doi:10.1001/jama.2018.18938.  https://jamanetwork.com/journals/jama/article-abstract/2723062

Clinical trials involve evaluating and validating new therapies in humans and represent the fundamental means of making progress in cancer care. The oncology community has made significant improvements in treating most cancers and, in some cases, has developed cures, such as for testicular cancer, Hodgkin disease, and acute lymphocytic leukemia. In an even larger number of cancers, researchers and clinicians have succeeded in making cancer a chronic disease that people die with rather than of. Each of these therapeutic discoveries represents the results of clinical trials.  Many of these advances were made possible in large part through the Clinical Trials Program at the National Cancer Institute (NCI). This program began in 1955,1 and since then has changed substantially in its approach to the design, coordination, and implementation of clinical trials. The past 10 years, in particular, have seen a transformational reworking of the NCI’s clinical trials infrastructure. The NCI National Clinical Trials Network (NCTN) now includes more than 3000 study sites across the United States and Canada and each year enrolls more than 20 000 children and adults with all types of cancer in clinical trials. The NCTN portfolio includes studies across the cancer research continuum, from first-in-human trials of new agents, to evaluations of new diagnostic and therapeutic techniques, to trials evaluating cancer prevention and symptom management. The infrastructure provides a broad range of support services, including centralized institutional review boards; clinical trials monitoring, data acquisition, and management systems; tissue banks; and quality-control centers for imaging and radiation therapy.

Rethinking Clinical Trials
Cancer clinical trials have important and increasing challenges. In response, NCI, as the leading funder of academic cancer clinical trials, has made modernizing clinical trials a key area of focus.

In addition to a strong recommitment to using the best basic science to drive trials and providing infrastructure for the training of the next generation of cancer clinical trialists through support for early-stage investigators, NCI is using specific strategies to overcome barriers impeding the execution of clinical trials.

Reduce Financial Pressures of Clinical Trials
The average per-patient cost of conducting a clinical trial has increased sharply over the last 2 decades, driving an escalation of the total costs of drug discovery and development. Once a drug is approved, the high costs of trials are then passed on to patients in the form of higher drug prices.  The NCI is therefore focused on “right-sizing” trials to answer essential questions about the efficacy of new treatments with fewer patients. For example, in some trials of highly active agents, it may be possible to forgo traditional control group interventions in favor of well-annotated “synthetic” controls created with data from previous trials. The NCI is also exploring the use of novel end points that reflect the mechanism of action of the drug under study through “pragmatic trials” that are conducted in clinical practice settings and through augmented annotation and aggregation of new and existing trials data to answer relevant clinical questions without additional enrollment.

Conduct Trials That Complement Those of Industry
The emergence of industry as the majority funder of cancer clinical trials has led to redundancies in the portfolio of novel agents in development, with the unintended consequence of crowding out some meritorious ideas for therapy in the search for more commercially lucrative ones. Consequently, the NCI has been positioning its clinical trials portfolio to complement, rather than compete with, efforts from industry.

National Cancer Institute–supported trials are prioritized scientifically by leaders in oncology research. Trials sponsored by the NCI that complement those supported by industry, can, for example, focus on low-prevalence cancers for which there is limited commercial incentive to sponsor clinical investigations, such as pediatric cancers, uncommon cancers, rare subtypes of more common tumors, and special patient populations (eg, patients with HIV or >75 years). The NCI-funded Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART) (NCT02834013) national trial, for example, is the first immunotherapy trial focused on rare cancers.  The NCI has supported clinical trials focused on deescalation of therapeutic intensity, which is an important topic for patients but typically of less interest to industry. For example, the Trial Assigning Individualized Options for Treatment (Rx) (TAILORx)4 and the International Duration Evaluation of Adjuvant Therapy (IDEA)5 trials showed that certain patients with breast and colorectal cancer, respectively, may be safely treated with less chemotherapy than previously recommended. In addition, the NCI prioritizes complex multiagent and multimodality (eg, radiation therapy, surgery, and chemotherapy) trials, especially those involving established (off-patent) agents, such as taxanes and corticosteroids. Moreover, the NCI supports a substantial portfolio of supportive care, cancer prevention, and screening studies that are not extensively supported by commercial sponsors, including studies of breast imaging modalities (eg, TMIST [NCT03233191]).

Facilitate Access to Investigational Agents
The NCI has created partnerships with industry, pioneering a shared intellectual property framework and an efficient mechanism for accelerating clinical trial proposal review. The NCI Formulary facilitates arrangements between pharmaceutical companies and investigators at NCI-designated cancer centers to expedite access to promising novel combinations of anticancer investigational agents sourced from multiple companies for use in preclinical and clinical studies.

Base Trials on Molecular Alterations
A key challenge and a sign of scientific progress involves the recognition that individual cancers, even of the same histological subtype, are molecularly heterogenous. These diseases are generally not well served by large, one-size-fits-all trials. Instead, the NCI has developed novel types of trials that enroll participants based on their molecular alterations, rather than their disease type. This approach limits these trials to patients who are most likely to benefit from a specific treatment and reduces the size of the trials to the smallest number of patients needed to demonstrate therapeutic efficacy. These trial designs often use “Master Protocols” to evaluate multiple classes of therapeutic agents simultaneously. Examples include NCI Molecular Analysis for Therapy Choice (NCI-MATCH) (NCT02465060), which is evaluating a pharmacopoeia of molecularly targeted agents based on the presence of specific tumor mutations in a disease-agnostic fashion, Lung Cancer Master Protocol (Lung-MAP) (NCT02154490), and NCI-COG Pediatric MATCH.

Improve Accrual Rates
An ongoing challenge is low accrual to clinical trials, especially among underserved populations. Only a small fraction of eligible adult patients with cancer are able to participate in clinical trials. Clinical research has traditionally been conducted at academic medical centers, primarily cancer centers. But the populations that cancer centers reach are less diverse than the population overall. Because most patients receive cancer care in community settings, the NCI established the NCI Community Oncology Research Program (NCORP) to bring cancer prevention and treatment trials to minority and underserved patient populations in a variety of health care delivery settings in their own communities. NCORP gives patients access to trials in which they might not otherwise be able to participate and not only increases the generalizability of study findings but also illuminates potential disparities in outcomes. The NCI-MATCH trial, for example, is available at 1100 sites across the country through NCTN and NCORP, leading to enrollment that better reflects the overall patient population.

Better Understand the Current Clinical Trials Portfolio
Active management of the NCI portfolio is critical to identifying and prioritizing clinical research opportunities, avoiding duplicative studies, and monitoring accrual and performance of ongoing trials. The NCI Clinical Trials Reporting Program (CTRP) database contains regularly updated information, including accrual, on all NCI-supported interventional clinical trials. It includes trials directly funded by NCI grants and contracts, as well as trials funded by industry and other sponsors that use the infrastructure of NCI-designated cancer centers. For dynamic areas of clinical investigation, such as immuno-oncology, CTRP data can help guide national efforts by enabling cancer trialists to actively identify new trials and monitor trends over time.

Future of NCI-Supported Clinical Trials
Collectively, these efforts demonstrate the ways in which NCI has continued to modernize its approach to supporting scientifically rigorous clinical trials. Tremendous opportunity and responsibility come with clinical trials. Patients participating in clinical trials must be assured that they are receiving the best possible care, that trial results will be shared with them in a timely manner, and that the trials are testing only the strongest new research concepts.  National Cancer Institute–supported clinical trials have adopted a more comprehensive, patient-centric approach that includes patients’ assessments of their tolerability of therapy and quality of life, both of which directly affect prognosis, and will continue to evolve. Continued progress will require a renewed awareness that cancer is not merely “a tumor encased in a human,” but rather a problem of a unique individual seeking a better outcome.

Ovarian Cancer Surgery — Heed This LION’s Roar. EL Eisenhauer and DS Chi. N Engl J Med 2019; 380:871-873  DOI: 10.1056/NEJMe1900044 https://www.nejm.org/doi/full/10.1056/NEJMe1900044

Most women with ovarian cancer will have metastatic disease at diagnosis, and their symptoms and survival will depend on whether their abdominal tumor can be controlled. Death from ovarian cancer most often occurs from progression of abdominal disease, as a result of either bowel obstruction or the consequences of malnutrition. Removal of all visible disease is the goal of primary cytoreduction and is consistently associated with improved survival in randomized trials.1 The nonvisible, microscopic tumor that remains is targeted with subsequent chemotherapy.  Pelvic and aortic lymph nodes that appear normal frequently harbor microscopic metastases. For several decades, considerable debate has focused on whether these lymph nodes should be systematically removed during primary surgery. Existing dogma suggests that these nodes may be a “pharmacologic sanctuary,” an idea born from observations after second-look laparotomy that many nodes still contained tumor that had not been eliminated by primary chemotherapy. A large number of investigations, including retrospective series, population studies, and reanalyses of prospective trials, have reported that systematic lymphadenectomy is associated with improved survival. One randomized trial did not show a survival benefit, but it was limited by its design and inclusion criteria. In this issue of the Journal, Harter and colleagues show in their LION (Lymphadenectomy in Ovarian Neoplasms) trial how meticulous trial design can help overcome many inherent confounders. Their trial effectively shows that systematic removal of these lymph nodes after maximal cytoreduction does not improve survival and may cause additional harm.  Their novel trial design resolved the criticisms of many previous studies. Specifically, surgical quality was assessed before centers were allowed to participate. To focus on the effect of systematic lymphadenectomy alone on survival, only women with advanced ovarian cancer who had undergone successful removal of all visible intraperitoneal disease underwent randomization, and the trial excluded women with visibly involved nodes. Lymph nodes were viewed directly, by opening the retroperitoneal space from the inguinal ligament to the renal vein, rather than simply palpated. Treatment (lymphadenectomy or no lymphadenectomy) was assigned only after complete visible cytoreduction, effectively blinding the assessment of eligibility. This was essential, because it has been difficult in other studies to distinguish whether lymphadenectomy had an independent effect on survival or was a surrogate for a more complete cytoreduction (i.e., was it just that more comprehensive cytoreductive procedures also included a lymphadenectomy?).  Women in the lymphadenectomy group had more complications, including repeat laparotomy. High surgical completeness was necessary to limit the effect of residual disease, and these patients had extensive surgery with a high rate of resection of bowel, spleen, and porta hepatis disease. Of the 1865 women registered, only 25% were excluded because of incomplete resection. The most common reason for repeat laparotomy was bowel leak or fistula, and the authors postulate that lymphadenectomy may have increased this risk by extending an otherwise complex procedure. Since a high number of repeat laparotomies were related to bowel complications, this may speak more to the heterogeneous risks of the bowel resections used to achieve complete cytoreduction in ovarian cancer than to a direct effect of lymphadenectomy. However, without an improvement in survival, any potential complications from systematic lymph-node dissection should be avoided.  Excellent outcomes were achieved in the patients selected for randomization, with a median progression-free survival of 26 months, a median overall survival of 67 months, and no significant difference between the groups. The previous trial by Panici and colleagues had shown improvement in progression-free (but not overall) survival among patients undergoing lymphadenectomy.7 In the LION trial, investigators did not specify a standard follow-up schedule for visits and scans in their article, but any potential differences were not reflected in overall survival. The absence of a difference in overall survival between the two groups in this trial is consistent with the concept that it is the inability to control intraabdominal disease that is the most frequent cause of ovarian cancer–related illness and death. Moreover, any potentially increased rate of disease recurrence in the lymph nodes did not affect survival among these women.  Women with ovarian cancer in whom complete primary cytoreduction is achieved have the best prognosis and longest survival. The procedures required to achieve complete cytoreduction already have attendant risks, and eliminating ineffective techniques such as systematic lymphadenectomy is prudent to improve patients’ overall recovery. Along the way, we may also have learned a bit about how difficult it can be to overcome our assumptions without a properly controlled trial design.

REVIEW: The role of menopausal hormone therapy in women with or at risk of ovarian and breast cancers: Misconceptions and current directions.  SM Temkin, A Mallen, E Bellavance, L Rubinsak, RM Wenham.  Cancer 125, (4) 2019, 499-514. https://onlinelibrary.wiley.com/doi/10.1002/cncr.31911 https://doi.org/10.1002/cncr.31911

For women who are candidates for menopausal hormone therapy (MHT), estrogen can provide relief from symptomatic menopause, decrease rates of chronic illnesses, and improve health‐related quality of life. However, confusion surrounds the evidence regarding the impact of exogenous estrogen and progesterone on the breast and ovary. Available data regarding the risks of MHT (estrogen and/or progestin) related to the development of breast and ovarian cancer are often inconsistent or incomplete. Modern molecular and genetic techniques have improved our understanding of the heterogeneity of breast and ovarian cancer. This enhanced understanding of the disease has impacted our understanding of carcinogenesis. Treatment options have evolved to be more targeted toward hormonal therapy for certain subtypes of disease, whereas cytotoxic chemotherapy remains the standard for other histological and molecular subtypes. The role of MHT in the breast and ovarian cancer survivor, as well as women who are at high risk for the development of hereditary breast and ovarian cancer, remains controversial despite evidence that this treatment can improve quality of life and survival outcomes. Through this article, we examine the evidence for and against the use of MHT with a focus on women who have or are at high risk for breast and ovarian cancer.

Mismatch repair deficiency identifies patients with highintermediate–risk (HIR) endometrioid endometrial cancer at the highest risk of recurrence: A prognostic biomarker.  FJ Backes, J Haag, CM Cosgrove, A, DE Cohn, PJ Goodfellow.  Cancer 125, (3:) 2019 398-405. https://onlinelibrary.wiley.com/doi/10.1002/cncr.31901  https://doi.org/10.1002/cncr.31901

Background  The objective of this study was to assess the correlation between mismatch repair (MMR) status, disease recurrence patterns, and recurrence‐free survival (RFS) in patients with high‐intermediate–risk (HIR) endometrioid endometrial cancer (EEC).

Methods  A single‐institution chart review for consecutive patients who were diagnosed with ECC between 2007 and 2016 was undertaken. Tumor MMR status was determined for all patients based on reported findings for mutL homolog 1 (MLH1), postmeiotic segregation (PMS2), mutS homolog 2 (MSH2), and MSH6 immunohistochemistry; and defective MMR (dMMR) status was defined as the lack of expression of at least 1 of these proteins. Patients were classified with HIR EEC according to criteria used for Gynecologic Oncology Group study 249. The factors associated with recurrence were assessed by logistic regression. RFS and associated factors were assessed by Kaplan‐Meier survival analysis and Cox proportional‐hazards models.

Results  In total, 197 patients who had HIR EEC (64 with dMMR and 133 with intact MMR [iMMR]) were identified, of whom 32 (16.2%) developed recurrent disease. The median follow‐up was 54 months. The recurrence rate for women who had dMMR was 28% compared with 10.5% for those who had iMMR (P = .002), independent of the type of adjuvant therapy they received. The increase in distant recurrences among patients who had dMMR was even more pronounced (14.1% vs 3%; P = .003). The estimated 5‐year RFS was 66% for women who had dMMR compared with 89% for those who had iMMR (P = .001). Excluding isolated vaginal recurrences, the difference in 5‐year RFS was 73.5% versus 95%, respectively (P = .0004).

Conclusions  Patients who had HIR EEC with dMMR had increased rates of recurrence and decreased RFS compared with those who had HIR EEC with iMMR, despite the receipt of similar adjuvant treatment. The current findings highlight the need for alternative treatment options and the importance of MMR status as a biomarker for patients with HIR EEC.

Analgesic Use and Ovarian Cancer Risk: An Analysis in the Ovarian Cancer Cohort Consortium

B Trabert, EM Poole, E White, K Visvanathan, H-OAdami, GL Anderson, TM Brasky, LA Brinton, RT Fortner, M Gaudet, P Hartge, J Hoffman-Bolton, M Jones, JV Lacey, Jr., SC Larsson, GG Mackenzie, LJ Schouten, DP Sandler, K O’Brien, AV Patel, U Peters, A Prizment, K Robien, VW Setiawan, A Swerdlow, PA van den Brandt, E Weiderpass, LR Wilkens, A Wolk, N Wentzensen, SS Tworoger.  JNCI: 111, (2) 2019, 137–145, https://academic.oup.com/jnci/article/111/2/137/5026198   https://doi.org/10.1093/jnci/djy100

Background  Aspirin use is associated with reduced risk of several cancers. A pooled analysis of 12 case–control studies showed a 10% decrease in ovarian cancer risk with regular aspirin use, which was stronger for daily and low-dose users. To prospectively investigate associations of analgesic use with ovarian cancer, we analyzed data from 13 studies in the Ovarian Cancer Cohort Consortium (OC3).

Methods  The current study included 758 829 women who at study enrollment self-reported analgesic use, among whom 3514 developed ovarian cancer. Using Cox regression, we assessed associations between frequent medication use and risk of ovarian cancer. Dose and duration were also evaluated. All statistical tests were two-sided.

Results  Women who used aspirin almost daily (≥6 days/wk) vs infrequent/nonuse experienced a 10% reduction in ovarian cancer risk (rate ratio [RR] = 0.90, 95% confidence interval [CI] = 0.82 to 1.00, P = .05). Frequent use (≥4 days/wk) of aspirin (RR = 0.95, 95% CI = 0.88 to 1.03), nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs; RR = 1.00, 95% CI = 0.90 to 1.11), or acetaminophen (RR = 1.05, 95% CI = 0.88 to 1.24) was not associated with risk. Daily acetaminophen use (RR = 1.28, 95% CI = 1.00 to 1.65, P = .05) was associated with elevated ovarian cancer risk. Risk estimates for frequent, long-term (10+ years) use of aspirin (RR = 1.15, 95% CI = 0.98 to 1.34) or nonaspirin NSAIDs (RR = 1.19, 95% CI = 0.84 to 1.68) were modestly elevated, although not statistically significantly so.

Conclusions  This large, prospective analysis suggests that women who use aspirin daily have a slightly lower risk of developing ovarian cancer (∼10% lower than infrequent/nonuse)—similar to the risk reduction observed in case–control analyses. The observed potential elevated risks for 10+ years of frequent aspirin and NSAID use require further study but could be due to confounding by medical indications for use or variation in drug dosing.

Antibodies Against Chlamydia trachomatis and Ovarian Cancer Risk in Two Independent Populations.  B Trabert,  T Waterboer,  A Idahl,  N Brenner, LA Brinton,  J Butt,  SB Coburn,  P Hartge, K Hufnagel, FInturrisi, J Lissowska,  A Mentzer,  B Peplonska, ME Sherman, GS Wills, SC Woodhall, M Pawlita, N Wentzensen.  JNCI: 111(2) 2019, 129–136, https://academic.oup.com/jnci/article/111/2/129/5001107 https://doi.org/10.1093/jnci/djy084

Background  Pelvic inflammatory disease (PID) has been associated with ovarian cancer risk. To clarify the role of Chlamydia trachomatis and other infectious agents in the development of ovarian cancer, we evaluated the association of serologic markers with incident ovarian cancer using a staged approach in two independent populations.

Methods  Studies included: 1) a case–control study in Poland (244 ovarian cancers/556 control subjects) and 2) a prospective nested case–control study in the PLCO Cancer Screening Trial (160 ovarian cancers/159 control subjects). Associations of serologic marker levels with ovarian cancer risk at diagnostic as well as higher thresholds, identified in Poland and independently evaluated in PLCO, were estimated using multivariable adjusted logistic regression.

Results  In the Polish study, antibodies (based on laboratory cut-point) against the chlamydia plasmid-encoded Pgp3 protein (serological gold standard) were associated with increased ovarian cancer risk (adjusted odds ratio [OR] = 1.63, 95% confidence interval [CI] = 1.20 to 2.22); when a positive result was redefined at higher levels, ovarian cancer risk was increased (cut-point 2: OR = 2.00, 95% CI = 1.38 to 2.89; cut-point 3 [max OR]: OR = 2.19, 95% CI = 1.29 to 3.73). In the prospective PLCO study, Pgp3 antibodies were associated with elevated risk at the laboratory cut-point (OR = 1.43, 95% CI = 0.78 to 2.63) and more stringent cut-points (cut-point 2: OR = 2.25, 95% CI = 1.07 to 4.71); cut-point 3: OR = 2.53, 95% CI = 0.63 to 10.08). In both studies, antibodies against other infectious agents measured were not associated with risk.

Conclusions  In two independent populations, antibodies against prior/current C. trachomatis (Pgp3) were associated with a doubling in ovarian cancer risk, whereas markers of other infectious agents were unrelated. These findings lend support for an association between PID and ovarian cancer.